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Higher-order memory CD8 T cells are crucial in providing immunity against common pathogens that reinfect the host or are generated by repeated vaccination. In this study, we analyzed peripheral blood from septic patients and show that memory CD8 T cells with defined Ag specificity for recurring CMV infection proliferate less than bulk populations of central memory CD8 T cells. Using TCR-transgenic T cells to generate 1\u00b0 and higher-order (quaternary [4\u00b0]) memory T cells within the same host, we demonstrate that the susceptibility and loss of both memory subsets are similar after sepsis induction, and sepsis diminished Ag-dependent and -independent (bystander) functions of these memory subsets equally. Both the 1\u00b0 and 4\u00b0 memory T cell populations proliferated in a sepsis-induced lymphopenic environment; however, due to the intrinsic differences in baseline proliferative capacity, expression of receptors (e.g., CD127\/CD122), and responsiveness to homeostatic cytokines, 1\u00b0 memory T cells become overrepresented over time in sepsis survivors. Finally, IL-7\/anti\u2013IL-7 mAb complex treatment early after sepsis induction preferentially rescued the proliferation and accumulation of 1\u00b0 memory T cells, whereas recovery of 4\u00b0 memory T cells was less pronounced. Thus, inefficient recovery of repeatedly stimulated memory cells after polymicrobial sepsis induction leads to changes in memory T cell pool composition, a notion with important implications in devising strategies to recover the number and function of pre-existing memory CD8 T cells in sepsis survivors.<\/jats:p>","DOI":"10.4049\/jimmunol.2200676","type":"journal-article","created":{"date-parts":[[2023,1,2]],"date-time":"2023-01-02T14:56:10Z","timestamp":1672671370000},"page":"168-179","source":"Crossref","is-referenced-by-count":7,"title":["Inefficient Recovery of Repeatedly Stimulated Memory CD8 T Cells after Polymicrobial Sepsis Induction Leads to Changes in Memory CD8 T Cell Pool Composition"],"prefix":"10.1093","volume":"210","author":[{"given":"Steven J","family":"Moioffer","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Iowa , Iowa City, IA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1517-8541","authenticated-orcid":false,"given":"Roger R","family":"Berton","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Iowa , Iowa City, IA"},{"name":"Interdisciplinary Program in Immunology, University of Iowa , Iowa City, IA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8308-127X","authenticated-orcid":false,"given":"Patrick W","family":"McGonagill","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Iowa , Iowa City, IA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3107-3961","authenticated-orcid":false,"given":"Isaac J","family":"Jensen","sequence":"additional","affiliation":[{"name":"Columbia University Irving Medical Center , New York, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7205-9859","authenticated-orcid":false,"given":"Thomas S","family":"Griffith","sequence":"additional","affiliation":[{"name":"Department of Urology, University of Minnesota , Minneapolis, MN"},{"name":"Minneapolis Veterans Affairs Health Care System , Minneapolis, MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3180-2439","authenticated-orcid":false,"given":"Vladimir P","family":"Badovinac","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Iowa , Iowa City, IA"},{"name":"Interdisciplinary Program in Immunology, University of Iowa , Iowa City, IA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,1,15]]},"reference":[{"key":"2025021101012704600_r1","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The third international consensus definitions for sepsis and septic shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"2025021101012704600_r2","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/S0140-6736(19)32989-7","article-title":"Global, regional, and national sepsis incidence and mortality, 1990\u20132017: analysis for the Global Burden of Disease Study","volume":"395","author":"Rudd","year":"2020","journal-title":"Lancet"},{"key":"2025021101012704600_r3","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1001\/jama.2014.5804","article-title":"Hospital deaths in patients with sepsis from 2 independent cohorts","volume":"312","author":"Liu","year":"2014","journal-title":"JAMA"},{"key":"2025021101012704600_r4","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1097\/CCM.0000000000003342","article-title":"Epidemiology and costs of sepsis in the United States\u2014an analysis based on timing of diagnosis and severity level","volume":"46","author":"Paoli","year":"2018","journal-title":"Crit. 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